In a briefing document released ahead of an advisory committee meeting next week, FDA safety reviewer Evelyn Mentari, MD, said that the drug showed "serious and potentially fatal safety issues" that could make it unapprovable.

And the agency's efficacy reviewer, John Marler, MD, concluded that methodological difficulties in the two pivotal trials conducted by alemtuzumab's sponsor, the Genzyme unit of Sanofi, undermined the drug's apparent effectiveness.

"Adequate and well-controlled studies need to be conducted to establish the efficacy of alemtuzumab," according to Marler.

In turn, the agency's final decisions need not follow advisory committee opinions, although they usually do.

Alemtuzumab, a monoclonal antibody targeting the CD52 protein, is already well-known in the oncology field as a leukemia drug, sold for many years under the name Campath. After studies indicated that it reduced MS relapses, Genzyme acquired rights to the drug. Last year, it halted commercial sales of Campath so that it could make alemtuzumab exclusively available as an MS treatment (although Genzyme is providing the drug free of charge to those leukemia patients who continue to do well on it).

In MS, the drug would be administered in two courses one year apart. Genzyme's two pivotal trials, CARE-MS-I and CARE-MS-II, both showed that the drug cut the annualized relapse rate in patients with relapsing-remitting MS by about 50% compared with beta-interferon (Rebig) treatment, one of two standard therapies for the condition (the other is glatiramer acetate, trade name Copaxone).

But Marler, in reviewing the data for efficacy, was concerned by several aspects of these studies.

"It is troublesome to see that so many patients were not assessed for baseline [disability] and were not treated until weeks after the randomization. Such delaying not only allowed patients to drop out before receiving any treatment and assessments when assigned treatment was undesired, but also effectively invalidated the baseline scores," he wrote.

This problem meant that CARE-MS-II's finding of a reduction in disability progression "was not validly established," Marler wrote. CARE-MS-I did not show a significant reduction in the investigators' analyses.

He also questioned the extent to which alemtuzumab reduced relapse rates relative to beta-interferon. "Patients' bias in preference of alemtuzumab, possible over-reporting of relapses in [the interferon] group and underreporting in alemtuzumab groups, and questions in interpreting the results in Study 324 [CARE-MS-II] have made accurate estimate of relapse rate impossible," Marler's report said.

"In summary, the two pivotal studies rendered more questions than answers. No sound statistical analysis can solve the problems from inadequately designed and poorly executed studies," the report continued. Marler suggested that new studies would need to be performed "to establish the possible efficacy of alemtuzumab."

Mentari's safety review focused on adverse events that had been reported in the CARE-MS investigators' published papers and meeting presentations.

These included the emergence of new autoimmune syndromes affecting the thyroid and blood and immune cell populations, and also some cases of thyroid cancer.

Among some 1,500 patients receiving alemtuzumab in the trials, 26 developed immune thrombocytopenia, three had autoimmune hemolytic anemia, two contracted autoimmune pancytopenia, and nearly 20% showed treatment-emergent nonmalignant thyroid disorders.

In addition, six patients on the drug developed thyroid cancers, versus none in the interferon groups.

Mentari did not identify excessive mortality with alemtuzumab. Nevertheless, she wrote that the drug's adverse effects, which also include others such as infusion reactions, were serious enough that only strong evidence of efficacy would justify approval.

The FDA's reviewers indicated that, if the drug is approved, it should come with a risk evaluation and mitigation strategy (REMS) that requires clinicians to monitor patients regularly for autoimmune disorders and other adverse effects, and to document the monitoring.

This requirement would be in addition to standard REMS components such as a medication guide, training for physicians, and registration of all patients prescribed the drug.

Advisory committee members will be asked to vote on whether the CARE-MS trials were adequate and well controlled; whether alemtuzumab appears to be effective for preventing relapses and disability; whether the safety issues preclude approval; whether the drug could be approved as a first-line MS therapy; and how the REMS should be designed.

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